2010
DOI: 10.2174/092986710791959747
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Identifying the Cellular Targets of Bioactive Small Molecules with Activity-Based Probes

Abstract: The renaissance of cell- or organism-based phenotypic assays has made subsequent target identification for bioactive small organic molecules an important aspect of current drug discovery. Among the many strategies available for target identification, derivatizing bioactive small molecules into activity-based probes has the main advantage of determining small molecule-protein interactions directly in the native environment where the target proteins maintain their three-dimensional structures, including all the … Show more

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Cited by 11 publications
(11 citation statements)
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References 94 publications
(142 reference statements)
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“…19, 20, 25 The general idea appears to have been first described over 20 years ago for the isolation of ACTH receptors, 39 and successfully implemented a few years later for isolation of a melanocyte-stimulating hormone receptor. 40 In both cases, biotin had been selected as the affinity purification agent because of its high affinity for streptavidin, which in principal would enable facile separation of a protein bearing a biotinylated ligand from non-target proteins.…”
Section: Discussionmentioning
confidence: 99%
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“…19, 20, 25 The general idea appears to have been first described over 20 years ago for the isolation of ACTH receptors, 39 and successfully implemented a few years later for isolation of a melanocyte-stimulating hormone receptor. 40 In both cases, biotin had been selected as the affinity purification agent because of its high affinity for streptavidin, which in principal would enable facile separation of a protein bearing a biotinylated ligand from non-target proteins.…”
Section: Discussionmentioning
confidence: 99%
“…19, 20 The isolated proteins are then separated and identified by bottom up mass spectrometry. There have been several reports in which compounds with K d 's of around 1 nM can be used to pull down target proteins in this manner from cell lysates.…”
Section: Introductionmentioning
confidence: 99%
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“…High-throughput experimental techniques for rapid evaluation of drug-target interactions have been developed, including cell-based phenotypic screens [45], binding affinity assays [46], in vitro modeling of ADMET (absorption, distribution, metabolism, excretion and toxicity) [47], activity-based probes [48] and transcriptional profiling [49]. However, the current screening capacities are still limited in testing the huge amount of possible compounds against hundreds of therapeutically relevant protein targets.…”
Section: Global Prediction Of Drug-target Interaction Networkmentioning
confidence: 99%
“…6, 7 While quantitative proteomic mass-spectrometry techniques have significantly aided the distinguishing of low-abundance protein targets from high abundance non-specific small molecule-protein interactions, 8 there remain fundamental drawbacks associated with affinity reagent based target identification strategies. Such projects are typically labor-intensive, with no guarantee of success.…”
Section: Introductionmentioning
confidence: 99%